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Oral idasanutlin in patients with polycythemia vera
Abstract
A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.
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“These results suggest that RG7388 has promising efficacy.366”
From p53: from understanding its structure to advances in therapeutic targeting (2026) · cites this paper as [366]
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“A phase I trial of RG7388 in high-risk polycythemia vera (PV) and essential thrombocythemia (ET) patients was subsequently conducted. The ORR was 58% (7/12) after 6 cycles of RG7388 monotherapy. Although DLTs did not occur in all patients, most patients had low-grade gastrointestinal disease.”
From p53: from understanding its structure to advances in therapeutic targeting (2026) · cites this paper as [366]
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Cited by
Small-molecule correctors and stabilizers to target p53
Fallatah, M. M. J., Law, F. V., Chow, W. A., & Kaiser, P. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.02.007 · Cited by 44
p53: from understanding its structure to advances in therapeutic targeting
Wang, W., Liu, X., Liu, H., Abolhassani, H., Yan, H., Zhang, H., & Wang, X. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02549-5 · Cited by 30
What do we need to know and understand about p53 to improve its clinical value?
Salomao, N., Karakostis, K., Hupp, T., Vollrath, F., Vojtesek, B., & Fahraeus, R. (2021) · The Journal of Pathology · doi:10.1002/path.5677 · Cited by 15
Metadata
- Authors
- Mascarenhas, J., Lu, M., Kosiorek, H., Virtgaym, E., Xia, L., Sandy, L., Mesa, R., Petersen, B., Farnoud, N., Najfeld, V., Rampal, R., Dueck, A., & Hoffman, R.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-08-08
- Volume
- 134
- Issue
- 6
- Pages
- 525-533
- ISSN
- 0006-4971
- 1528-0020
- Cited by
- 87
- References
- 4
- Language
- en
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